Though "insulin resistance" is likely to have multiple primary causes, the impairment in insulin's ability to promote skeletal muscle glucose transport and/or phosphorylation is a recurrent feature. A possible explanation for this observation is that a primary cause of either moderate glucose intolerance (ie, beta cell and/or hepatic defect) or a primary impairment in a major pathway of intracellular glucose disposal (ie, glycogen synthesis and/or glycolysis) may cause the full expression of the insulin resistance syndrome through a common biochemical pathway. Using primary cultures of adipose cells, Marshall and colleagues suggested that the desensitization of the glucose transport system in cells incubated with high levels of glucose and insulin required the metabolism of glucose in the hexosamine biosynthesis pathway. If such a regulatory pathway is operating in skeletal muscle in vivo and is capable of desensitizing the glucose transport system to insulin, it would represent an attractive unifying hypothesis for the presence of defective insulin action on glucose transport/phosphorylation in most insulin resistant states. In fact, increased routing of glucose carbons through the glucosamine pathway could result from a sustained elevation in intracellular fructose-6-phosphate concentrations due to either or both increased glucose availability, ie, chronic hyperglycemia/hyperinsulinemia, and decreased disposal through glycolysis and/or glycogen synthesis. Thus, the mechanism by which hyperglycemia begets impaired insulin action on glucose transport/phosphorylation may shed light on a more fundamental "feed-back control system" which down- regulates cellular glucose uptake in response to a sustained increase in the intracellular availability of hexose-phosphates. Our proposal will attempt to identify the sequential appearance of metabolic defects in hepatic and skeletal muscle glucose metabolism in a diabetic model of chronic hyperglycemia and moderate hypoinsulinemia and the time-course of their reversal following correction of chronic hyperglycemia by phlorizin treatment. In particular, tracer methodologies recently developed in the conscious rat should allow us to clarify the role of defective glucose-induced suppression of hepatic gluconeogenesis/glycogenolysis and of impaired insulin-mediated inhibition of skeletal muscle glycogenolysis to the development of glucose-induced insulin resistance. We will also examine whether the metabolism of glucose through the glucosamine pathway has the important regulatory role in in vivo glucose-induced desensitization which was suggested in primary culture of adipose cells and whether such a desensitization can be induced through the impairment of intracellular glucose disposal even in the absence of sustained hyperglycemia.